Phosphodiesterases and the Effects of Forskolin

  • Michael Gralinski
  • Liomar A. A. Neves
  • Olga Tiniakova
Living reference work entry

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and/or cGMP. They function with adenyl and guanylyl cyclases to regulate the amplitude and duration of responses triggered by the second messengers cAMP and cGMP. The enzyme phosphodiesterase (PDE) exists in various forms. At least 11 families of phosphodiesterases have been identified (Torphy and Page 2000; Francis et al. 2001; Maurice et al. 2003; Lugnier 2006). The properties and functions of GAF domains in cyclic nucleotide phosphodiesterases are reviewed by Zoraghi et al. (2004).

Keywords

Adenylate Cyclase Corpus Cavernosum Cyclic Nucleotide Phosphodiesterase Pulmonary Artery Smooth Muscle Cell Human Corpus Cavernosum 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Further Reading

Phosphodiesterases

  1. Francis SH, Turko IV, Corbin JD (2001) Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol 65:1–52PubMedGoogle Scholar
  2. Hofmann F, Biel M, Kaupp UB (2006) International Union of Pharamcology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels. Pharmacol Rev 57:455–462Google Scholar
  3. Lugnier C (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109:366–398Google Scholar
  4. Maurice DH, Palmer D, Tilley DG, Dunkerley HA, Netherton SJ, Raymond DR, Elbatarny HS, Jimmo SL (2003) Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol Pharmacol 64:533–546Google Scholar
  5. Mongillo M, McSorley T, Evellin S, Sood A, Lissandron V, Terrin A, Huston E, Hannawacker A, Lohse MJ, Pozzan T, Houslay MD, Zaccolo M (2004) Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases. Circ Res 95:67–75Google Scholar
  6. Snyder PB, Esselstyn JM, Loughney K, Wolda SL, Florio VA (2005) The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J Lipid Res 46:494–503PubMedGoogle Scholar
  7. Torphy TJ, Page C (2000) Phosphodiesterases: the journey towards therapeutics. Trends Pharmacol Sci 21:157–159PubMedGoogle Scholar
  8. Zhang KYJ, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, Neiman J, West BL, Zhang C, Milburn MV, Kim SH, Schlessinger J, Bollag G (2004) A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell 15:279–286PubMedGoogle Scholar
  9. Zoraghi R, Corbin JD, Francis SH (2004) Properties and functions of GAF domains in cyclic nucleotide phosphodiesterases and other proteins. Mol Pharmacol 65:267–278PubMedGoogle Scholar

Inhibition of Phosphodiesterase

  1. Boudreau RJ, Drummond GI (1975) A modified assay of 3′,5′-cyclic-AMP phosphodiesterase. Anal Biochem 63:388–399PubMedGoogle Scholar
  2. Meskini N, Némoz G, Okyayuz-Baklouti I, Lagarde M, Prigent AF (1994) Phosphodiesterase inhibitory profile of some related xanthine derivatives pharmacologically active on the peripheral microcirculation. Biochem Pharmacol 47:781–788PubMedGoogle Scholar
  3. Pichard AL, Cheung WY (1976) Cyclic 3′:5′-nucleotide phosphodiesterase. Interconvertible multiple forms and their effects on enzyme activity and kinetics. J Biol Chem 251:5726–5737PubMedGoogle Scholar
  4. Prigent AF, Némoz G, Yachaoui Y, Pageaux JF, Pacheco H (1981) Cyclic nucleotide phosphodiesterase from a particulate fraction of rat heart. Solubilization and characterization of a single enzymatic form. Biochem Biophys Res Commun 102:355–364PubMedGoogle Scholar
  5. Prigent AF, Fougier S, Nemoz G, Anker G, Pacheco H, Lugnier C, Lebec A, Stoclet JC (1988) Comparison of cyclic nucleotide phosphodiesterase isoforms from rat heart and bovine aorta. Separation and inhibition by selective reference phosphodiesterase inhibitors. Biochem Pharmacol 37:3671–3681PubMedGoogle Scholar
  6. Reinsberg L (1999) Personal CommunicationGoogle Scholar
  7. Terai M, Furihata C, Matsushima T, Sugimura T (1976) Partial purification of adenosine 3′,5′-cyclic monophosphate phosphodiesterase from rat pancreas in the presence of excess protease inhibitors. Arch Biochem Biophys 176:621–629PubMedGoogle Scholar
  8. Thompson WJ, Brooker G, Appleman MM (1974) Assay of cyclic nucleotide phosphodiesterases with radioactive substrates. In: Hardman JG, O’Malley BW (eds) Methods in enzymology, vol 38. Academic, New York, pp 205–212Google Scholar
  9. Younès A, Lukyanenko YO, Lyashkov AE, Lakatta EG, Sollott SJ (2011) A bioluminescence method for direct measurement of phosphodiesterase activity. Anal Biochem 417(1):36–40PubMedCentralPubMedGoogle Scholar
  10. Rich TC, Karpen JW (2005) High-throughput screening of phosphodiesterase activity in living cells. Methods Mol Biol 307:45–61PubMedGoogle Scholar

Description of Phosphodiesterase Isoforms Phosphodiesterase 1

  1. Abbott BM, Thompson PE (2006) Analysis of anti-PDE3 activity of 2-morpholinochromone derivates reveals multiple mechanisms of anti-platelet activity. Bioorg Med Chem Lett 16:969–973PubMedGoogle Scholar
  2. Adachi H, Kakiki M, Kishi Y (2005) Effects of a phosphodiesterase 3 inhibitor, olprinone, on rhythmical change in tension of human gastroepiploic artery. Eur J Pharmacol 528:137–143PubMedGoogle Scholar
  3. Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD (2003) β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A 100:940–945PubMedCentralPubMedGoogle Scholar
  4. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM (1998) Effects of sildenafil on the ralaxation of human corpus cavernosum tissue in vitro and the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 159:2164–2171PubMedGoogle Scholar
  5. Bernadelli P, Lorthiois E, Vergne F, Oliveira C, Mafroud AK, Proust E, Pham N, Ducrot P, Moreau F, Idrissi M, Tertre A, Bertin B, Coupe M, Chevalier E, Descours A, Berlioz-Seux F, Berna P, Li M (2004) Spiroquinazolinones as novel, potent and selective PDE7 inhibitors. Part 2: optimization of 5,8-disubstituted derivatives. Bioorg Med Chem Lett 14:4627–4631Google Scholar
  6. Bi Y, Stoy P, Adam L, He B, Krupinski J, Normandin D, Pongrac R, Seliger L, Watson A, Macor JE (2001) The discovery of novel, potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 11:2461–2464PubMedGoogle Scholar
  7. Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP (2006) The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther 318:840–848PubMedGoogle Scholar
  8. Chambers RJ, Abrams K, Garceau NY, Kamath AV, Manley CM, Lilley SC, Otte DA, Scott DO, Sheils AL, Tess DA, Vellekoop AS, Zhang Y, Lam KT (2006) A new chemical tool for exploring the physiological function of the PDE2 isozyme. Bioorg Med Chem Lett 16:307–310PubMedGoogle Scholar
  9. Chuang AT, Strauss JD, Murphy RA, Steers WD (1998) Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies cGMP-dependent relaxation in rabbit corpus cavernosum muscle in vitro. J Urol 160:257–261PubMedGoogle Scholar
  10. Cohen AH, Hanson K, Morris K, Fouty B, MacMurty IF, Clarke W, Rodman DM (1996) Inhibition of cyclic 3′-5′-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. J Clin Invest 97:172–179PubMedCentralPubMedGoogle Scholar
  11. Conti M, Richter W, Mehats C, Livera G, Park JY, Jin G (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278:5493–5496PubMedGoogle Scholar
  12. Corbin JD, Francis SH (1999) Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 274:13729–13732PubMedGoogle Scholar
  13. Corbin JD, Beasley A, Blount MA, Francis SH (2004) Verdenafil: structural basis for higher potency over sildenafil in inhibiting cCMP-specific phosphodiesterease-5 (PDE5). Neurochem Int 45:859–863PubMedGoogle Scholar
  14. Coudray C, Charon C, Komas N, Mory G, Diot-Dupuy F, Manganiello V, Ferre P, Bazin R (1999) Evidence for the presence of several phosphodiesterase isoforms in brown adipose tissue of Zucker rats: modulation of PDE2 by the fa gene expression. FEBS Lett 456:207–210PubMedGoogle Scholar
  15. Criuckshank JM (1993) Phosphodiesterase III inhibitors: longterm risks and short-term benefits. Cardiovasc Drugs Ther 7:655–660Google Scholar
  16. D’Armours MR, Granovsky AE, Artemyev NO, Cote RH (1999) Potency and mechanism of action of E4021, a type 5 phosphodiesterase isozyme-selective inhibitor, on the photoreceptor phosphodiesterase depend on the state of activation of the enzyme. Mol Pharmacol 3:508–514Google Scholar
  17. Epstein PM, Fiss K, Hachisu R, Andrenyak DM (1982) Interaction of calcium antagonists with cyclic AMP phosphodiesterase and calmodulin. Biochem Biophys Res Commun 105:1142–1149PubMedGoogle Scholar
  18. Galié N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simmoneau G (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157PubMedGoogle Scholar
  19. Giembycz MA (2002) Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far. Monaldi Arch Chest Dis 57:48–64PubMedGoogle Scholar
  20. Gillespie PG, Beavo JA (1989) Inhibition and stimulation of photoreceptor phosphodiesterases by dipyridamole and M&B 22,948. Mol Pharmacol 36:773–781PubMedGoogle Scholar
  21. Goraya TA, Cooper DMF (2005) Ca2+-calmodulin-dependent phosphodiesterase (PDE1): current perspectives. Cell Sign 17:789–797Google Scholar
  22. Hagiwara M, Endo T, Hidaka H (1984) Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle. Biochem Pharmacol 33:453–457PubMedGoogle Scholar
  23. Hambleton R, Krall J, Tikishvili E, Honeggar M, Ahmad F, Manganiello VC, Movsesian MA (2005) Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP hydrolytic activity in subcellular fractions of human myocardium. J Biol Chem 280:39168–39174PubMedGoogle Scholar
  24. Hosogai N, Hamada K, Tomita M, Nagashima A, Takahashi T, Sekizawa T, Mizutani T, Urano Y, Kuroda A, Sawada K, Ozaki T, Seki J, Goto T (2001) FR226807: a potent and selective phosphodiesterase type 5 inhibitor. Eur J Pharmacol 428:295–302PubMedGoogle Scholar
  25. Houslay MD, Sullivan M, Bolger GB (1998) The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting antiinflammatory and antidepressant actions. Adv Pharmacol 44:225–342PubMedGoogle Scholar
  26. Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signaling cross-talk, desensitization and compartmentalization. Biochem J 370:1–18PubMedCentralPubMedGoogle Scholar
  27. Huai G, Wang H, Sun Y, Kim HY, Liu Y, Ke H (2003) Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure 11:865–873PubMedGoogle Scholar
  28. Jeremy JY, Ballard SA, Naylor AM, Miller MAW, Angelini GD (1997) Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro. Br J Urol 79:958–963PubMedGoogle Scholar
  29. Jernigan NL, Walker BR, Resta TC (2004) Chronic hypoxia augments protein kinase G-mediated Ca2+ desensitization in pulmonary vascular smooth muscle through inhibition of RhoA/Rho kinase signaling. Am J Physiol 287:L1220–L1229Google Scholar
  30. Kakkar R, Raju RVS, Sharma RK (1999) Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1). Cell Mol Life Sci 55:1164–1185PubMedGoogle Scholar
  31. Kim NN, Huang YH, Goldstein I, Bischoff E, Traish AM (2001) Inhibition of cyclic GMP hydrolysis in human corpus cavernosum smooth muscle cells by vardenafil, a novel, selective phosphodiesterase type 5 inhibitor. Life Sci 69:2249–2256PubMedGoogle Scholar
  32. Komas N, Lugnier C, Le Bed A, Serradeil-Le Gal C, Barthelemy G, Stoclet JC (1989) Differential sensitivity to cardiotonic drugs of cyclic AMP phosphodiesterases isolated from canine ventricular and sinoatrial-enriched tissues. J Cardiovasc Pharmacol 14:213–220PubMedGoogle Scholar
  33. Liu H, Palmer D, Jimmo SL, Tilley DG, Dunkerley HA, Pang SC, Maurice DH (2000) Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclic AMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways. A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression in cells. J Biol Chem 275:26615–26624PubMedGoogle Scholar
  34. Lorthiois E, Bernadelli P, Vergne F, Oliveira C, Mafroud AK, Proust E, Heuze L, Moreau F, Idrissi M, Tertre A, Bertin B, Coupe M, Wrigglesworth R, Decours A, Soulard P, Berna P (2004) Spiroquinazolinones as novel, potent and selective PDE7 inhibitors. Part 1. Bioorg Med Chem Lett 14:4623–4626PubMedGoogle Scholar
  35. Loughney K, Hill TR, Florio VA, Uher L, Rosman GJ, Wolda SL, Jones BA, Howard ML, McAllister-Lucas LM, Sonnenburg WK, Francis SH, Corbin JD, Beavo JA, Ferguson K (1998) Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase. Gene 216:139–147PubMedGoogle Scholar
  36. Lugnier C (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109:366–398Google Scholar
  37. Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WGJ (2002) The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and cGMP binding. Proc Natl Acad Sci U S A 99:13260–13265PubMedCentralPubMedGoogle Scholar
  38. Masciarelli S, Horner K, Liu C, Park SH, Hinckley M, Hockman S, Nedachi T, Jin C, Conti M, Manganiello V (2004) Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility. J Clin Invest 114:196–205PubMedCentralPubMedGoogle Scholar
  39. Maurice DH, Palmer D, Tilley DG, Dunkerley HA, Netherton SJ, Raymond DR, Elbatarny HS, Jimmo SL (2003) Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol Pharmacol 64:533–546Google Scholar
  40. Mongillo M, McSorley T, Evellin S, Sood A, Lissandron V, Terrin A, Huston E, Hannawacker A, Lohse MJ, Pozzan T, Houslay MD, Zaccolo M (2004) Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases. Circ Res 95:67–75Google Scholar
  41. Nikolaev VO, Gambaryan S, Engelhardt S, Walter U, Lohse MJ (2005) Real-time monitoring of the PDE2 activity of live cells. J Biol Chem 280:1716–1719PubMedGoogle Scholar
  42. O’Donnell JM, Zhang HT (2004) Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 26:158–163Google Scholar
  43. Podzuweit T, Nennstiel P, Müller A (1995) Isozyme selective inhibition of cCMP-stimulated cyclic nucleotide phosphodiesterases by erythro-9-(2-hdroxy-3-nonyl) adenine. Cell Signal 7:733–738PubMedGoogle Scholar
  44. Qiu Y, Kraft P, Lombardi E, Clancy J (2000) Rabbit corpus cavernosum smooth muscle shows a different phosphodiesterase profile than human corpus cavernosum. J Urol 164:882–886PubMedGoogle Scholar
  45. Reinhardt RR, Chin E, Zhou J, Taira M, Murata T, Manganiello VC, Bondy CA (1995) Distinctive anatomical patterns of gene-expression for cCMP-inhibited cyclic nucleotide phosphodiesterases. J Clin Invest 95:1528–1538PubMedCentralPubMedGoogle Scholar
  46. Rosman GJ, Martins TJ, Sonnenburg WK, Beavo JA, Ferguson K, Loughney K (1997) Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3′,5′-cyclic nucleotide phosphodiesterase. Gene 191:89–95PubMedGoogle Scholar
  47. Rotella DP (2001) Phosphodiesterase type 5 inhibitors: discovery and therapeutic utility. Drugs Future 26:153–162Google Scholar
  48. Ruppert D, Weithmann KU (1982) HL 725, an extremely potent inhibitor of platelet phosphodiesterase and induced platelet aggregation. Life Sci 31:2037–2043PubMedGoogle Scholar
  49. Saenz de Tejada I, Angulo J, Cuevas P, Fernández A, Moncada I, Allona A, Lledó E, Körschen I, Niewöhner U, Haning H, Pages E, Bischoff E (2001) The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 13:282–290PubMedGoogle Scholar
  50. Schwabe U, Miyake M, Ohga Y, Daly JW (1976) 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711): a potent inhibitor of adenosine cyclic 3′,5′-monophosphate phosphodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol 11:900–911Google Scholar
  51. Sharma RK, Das SB, Lakshmikuttyamma A, Selvakumar P, Shrivastav A (2006) Regulation of calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1): review. Int J Mol Med 18:95–105PubMedGoogle Scholar
  52. Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG, Barnes PJ, Barnette MS, Giembycz MA (2004) Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol Pharmacol 66:1679–1689PubMedGoogle Scholar
  53. Soderling SH, Beavo SH (2000) Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol 12:174–179PubMedGoogle Scholar
  54. Stief CG, Uckert S, Becker AJ, Truss MC, Jonas U (1998) The effect of the specific phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo. J Urol 159:1390–1393PubMedGoogle Scholar
  55. Stoclet JC, Keravis T, Komas N, Lugnier C (1995) Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiovascular diseases. Expert Opin Invest Drugs 4:1081–1100Google Scholar
  56. Tantini B, Manes A, Fiumana E, Pignatti C, Guarnieri C, Zannoli R, Branzi A, Galié N (2005) Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 100:131–138PubMedGoogle Scholar
  57. Tenor H, Schudt C (1996) Analysis of isoenzyme profiles in cells and tissues by pharmacological methods. In: Schudt C, Dent G, Rabe KF (eds) Phosphodiesterase inhibitors. Handbook of immunopharmacology. Academic Press, London, pp 21–40Google Scholar
  58. Thompson CS, Mumtaz FH, Khan MA, Wallis RM, Mikhailidis DP, Morgan RJ, Angelini CD, Jeremy JY (2001) The effect of sildenafil on corpus cavernosal smooth muscle relaxation and cyclic GMP formation in the diabetic rabbit. Eur J Pharmacol 425:57–64PubMedGoogle Scholar
  59. Turko IV, Ballard SA, Francis SH, Corbin JD (1999) Inhibition of GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. Mol Pharmacol 56:124–130PubMedGoogle Scholar
  60. Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Kikawa K, Omori K (2001) Novel, potent, and selective phosphodiesterase 5 inhibitors: synthesis and biological activities of a series of 4-ary-1-isochinoline derivatives. J Med Chem 44:2204–2218PubMedGoogle Scholar
  61. Vergne F, Bernadelli P, Lorthiois E, Pham N, Proust E, Oliveira C (2004a) Discovery of thiadiazoles: a novel structural class of potent and selective PDE7 inhibitors: Part 2: metabolism-directed optimization studies towards orally bioavailable derivatives. Bioorg Med Chem Lett 14:4615–4621PubMedGoogle Scholar
  62. Vergne F, Bernadelli P, Lorthiois E, Pham N, Proust E, Oliveira C, Mafroud AK, Royer F, Wrigglesworth R, Schellhaas JK, Barvian MR, Moreau F, Idrissi M, Tertre A, Bertin B, Coupe M, Berna P, Soulard P (2004b) Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: design, synthesis and structure-activity relationship studies. Bioorg Med Chem Lett 14:4607–4613PubMedGoogle Scholar
  63. Vergne F, Bernadelli P, Lorthiois E, Pham N, Proust E, Oliveira C, Mafroud AK, Ducrot P, Wrigglesworth R, Berlioz-Seux F, Coleon F, Chevalier E, Moreau F, Idrissi M, Tertre A, Descours A, Berna P, Li M (2004c) Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 2: metabolism-directed optimization studies towards orally bioavailable derivatives. Bioorg Med Chem Lett 14:4615–4621PubMedGoogle Scholar
  64. Wallis RM, Corbin JD, Francis SH (1999) Tissue distribution of phosphodiesterase families and the effect of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 83:3C–12CPubMedGoogle Scholar
  65. Wang P, Wu P, Myers JG, Stamford A, Egan RW, Billah MM (2001) Characterization of human, dog and rabbit corpus cavernosum type 5 phosphodiesterases. Life Sci 68:1977–1987PubMedGoogle Scholar
  66. Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M (2005) Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol Pharmacol 68:1775–1781PubMedGoogle Scholar
  67. Yan C, Zhao AZ, Bentley JK, Beavo JA (1996) The calmodulin independent phosphodiesterase gene PDE1C encodes several functionally different splice variants in a tissue-specific manner. J Biol Chem 271:25699–25706PubMedGoogle Scholar
  68. Yanaka N, Kurosawa Y, Minami K, Kawai E, Omori K (2003) CGMP-phosphodiesterase activity is upregulated in response to pressure overload of rat ventricles. Biosci Biochem 67:073–079Google Scholar
  69. Yu S, Wolda SL, Frazier ALB, Florio VA, Martins TJ, Snyder PB, Harris EAS, McCaw KN, Farell CA, Steiner B, Bentley JK, Beavo JA, Ferguson K, Gelinas R (1997) Identification and characterisation of a human calmodulin-stimulated phosphodiesterase PDEB1. Cell Signal 9:519–529PubMedGoogle Scholar
  70. Zhang X, Feng Q, Cote RH (2005) Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Invest Ophthalmol Vis Sci 46:3060–3066PubMedCentralPubMedGoogle Scholar

Stimulation of Heart Membrane Adenylate Cyclase

  1. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analyt Biochem 72:248–254PubMedGoogle Scholar
  2. Caprioli J (1985) The pathogenesis and medical management of glaucoma. Drug Dev Res 6:193–215Google Scholar
  3. Caprioli J, Sears M (1983) Forskolin lowers intraocular pressure in rabbits, monkeys and man. Lancet 1:958–960PubMedGoogle Scholar
  4. Chang J, Hand JM, Schwalm S, Dervinis A, Lewis AJ (1984) Bronchodilating activity of forskolin in vitro and in vivo. Eur J Pharmacol 101:271–274PubMedGoogle Scholar
  5. Daly JW (1984) Forskolin, adenylate cyclase and cell physiology: an overview. Adv Cyclic Nucleotide Res 17:81–89Google Scholar
  6. Greenslade FC, Tobia AJ, Madison SM, Krider KM, Newquist KL (1979) Labetalol binding to specific alpha- and beta-adrenergic sites in vitro and its antagonism of adrenergic responses in vivo. J Mol Cell Cardiol 11:803–811PubMedGoogle Scholar
  7. Hubbard JW, Conway PG, Nordstrom LC, Hartman HB, Lebedinsky Y, O’Malley GJ, Kosley RW (1992) Cardiac adenylate cyclase activity, positive chronotropic and inotropic effects of forskolin analogs with either low, medium or high binding site activity. J Pharmacol Exp Ther 256:621–627Google Scholar
  8. Kebabian JW (1992) The cyclic AMP cascade: a signal transduction system. Neurotransmiss 8(2):1–4Google Scholar
  9. Lebedinsky Y, Nordstrom ST, Aschoff SE, Kapples JF, O’Malley GJ, Kosley RW, Fielding S, Hubbard JW (1992) Cardiotonic and coronary vasodilator responses to milrinone, forskolin, and analog P87–7692 in the anesthetized dog. J Cardiovasc Pharmacol 19:779–789PubMedGoogle Scholar
  10. Lindner E, Dohadwalla AN, Bhattacharya BK (1978) Positive inotropic and blood pressure lowering activity of a diterpene derivative isolated from Coleus forskohlii: Forskolin. Arzneim Forsch/Drug Res 28:284–289Google Scholar
  11. Metzger H, Lindner E (1981) The positive inotropic-acting forskolin, a potent adenylate-cyclase activator. Arzneim Forsch/Drug Res 31:1248–1250Google Scholar
  12. Salomon Y, Londos C, Rodbell M (1974) A highly sensitive adenylate cyclase assay. Analyt Biochem 58:541–548PubMedGoogle Scholar
  13. Seamon KB (1984) Forskolin and adenylate cyclase: new opportunities in drug design. Ann Rep Med Chem 19:293–302Google Scholar
  14. Seamon KB, Daly JW (1981a) Activation of adenylate cyclase by the diterpene forskolin does not require the guanine nucleotide regulatory protein. J Biol Chem 256:9799–9801PubMedGoogle Scholar
  15. Seamon KB, Daly JW (1981b) Forskolin: a unique diterpene activator of cyclic AMP-generating systems. J Cycl Nucl Res 7:201–224Google Scholar
  16. Seamon KB, Daly JW (1983) Forskolin, cyclic AMP and cellular physiology. Trends Pharmacol Sci 4:120–123Google Scholar
  17. Seamon KB, Padgett W, Daly JW (1981) Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci U S A 78:3363–3367PubMedCentralPubMedGoogle Scholar
  18. Seamon KB, Daly JW, Metzger H, de Souza NJ, Reden J (1983) Structure activity relationships for activation of adenylate cyclase by the diterpene forskolin and its derivates. J Med Chem 26:436–439PubMedGoogle Scholar
  19. Seamon KB, Vaillancourt R, Edwards M, Daly JW (1984a) Binding of [3H]forskolin to rat brain membranes. Proc Natl Acad Sci U S A 81:5081–5085PubMedCentralPubMedGoogle Scholar

3H-Forskolin Binding Assay

  1. Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (K I) and the concentration of inhibitor which causes 50 percent inhibition (IC 50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108PubMedGoogle Scholar
  2. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  3. Seamon KB, Vaillancourt R, Edwards M, Daly JW (1984b) Binding of [3H]forskolin to rat brain membranes. Proc Natl Acad Sci U S A 81:5081–5085PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Michael Gralinski
    • 1
  • Liomar A. A. Neves
    • 1
  • Olga Tiniakova
    • 1
  1. 1.CorDynamics, Inc.ChicagoUSA

Personalised recommendations